The invention relates to compositions comprising red rice fermentation products, that can be used as dietary supplements and/or therapeutic medicaments. For example, the compositions can be used to lower serum cholesterol and triglycerides in mammals. Further, the invention relates to methods of treating cardiovascular disorders and other diseases using the red rice fermentation products. In addition, the invention relates to particular Monascus strains that yield fermentation products with the desired biological activities.
Red Rice in Ancient China
Red rice is known mostly for its use in food as a preservative and colorant, and its uses in the dye industry. Red rice (known in Chinese as Hung-ch'u or Hongqu) has also been known and used for hundreds of years in China in rice wine making and as a food preservative. In addition, red rice has been known as an ancient Chinese medicine or an ingredient in certain ancient Chinese prescriptions.
Red Rice was first used around the time of the Han Dynasty. Tao Gu, who lived in the age of Wudai after the Tang Dynasty, recorded "Red Yeast Rice Cooked with Meat," in Qing Yi Lu. The method of making Red Rice was originally recorded in T'ien Kyng K'ai Wu and Pen Ts'ao Kang Mu, A detailed description of the medical applications of red rice was provided in the ancient Chinese pharmacopoeia, Pen Ts'ao Kang Mu, which was published during the Ming dynasty (1368-1644). In Pen Ts'ao Kang Mu, Red Rice is described as mild, nonpoisonous, and useful for treating indigestion and diarrhea Red Rice is also described as useful for improving blood circulation and promoting the health of the spleen and stomach. Furthermore, several "prescriptions" using red rice for treating aliments, such as indigestion, diarrhea, and heart and abdominal pains, are also provided in this ancient work. In accordance with the Traditional Chinese Medicine Standard set forth in Pharmacopoeia of People's Republic of China and the Traditional Chinese Medicine standard of Beijing, Nei Monggol, Shadog Provice, Jiangsu Province and Hunan province, etc., Red Rice is specified to be used as a traditional Chinese medicine. Furthermore, in the textbooks of Chinese universities and colleges such as Food Additives and Food Chemistry, Red Rice is considered as additives for food and beverages, and has been widely used in the food processing industry for the production of such items as fermented bean curd, beer, and meat.
In an abbreviated English translation of Pen Ts'ao Kang Mu published in 1911, red rice is described as useful for fermentation, and having medicinal value in the treatment of postpartum difficulties in women and dyspeptic conditions of children (Stuart, M. D., in "Chinese Materia Medica--Vegetable Kingdom," page 233-234, republished in 1979 by Southern Materials Center, Inc., Taipei, Republic of China). Red rice, as described in Pen Ts'ao Kang Mu, was subsequently recognized to be the fungal species known as Monascus purpureus Went (Read, B. E., 1936, Chinese Medicinal Plants from the Pen Ts'ao Kang Mu, 3rd edition, published by Peking National History Bulletin; Klein, G., 1932, Handbuch der Pflanzenanalyse II, p. 1422-1423, Wien, Verlag von Julius Springer).
The manufacture of red rice is taught in another publication from the Ming dynasty, Tien Kung K'ai Wu by Sung Ying-Hsing, which was published in 1637 A.D. (see pages 291-294 in English translation of this ancient writing, "Tien Kung K'ai Wu--Chinese technology in the seventeenth century," translated by E-tu Zen Sun and Shiou-Chuan Sun, The Pennsylvania State University Press 1966). Red rice is described therein as useful for preserving the color and taste of fish or meat. The manufacturing process used red wine mash and cooked nonglutinous rice as starting materials. The method of making red rice by allowing the fungus to grow on the surface of cooked rice was also recorded by Voderman (1894, Analecta ob Cromatologisch Gebied. II. Geneesh, Fylschrift voor Ned. Indie, 35, No.5).
Modernly, red rice, the fermentation product of Monascus species, is still used in traditional Chinese medicine, wine making and food coloring in Asia and Asian communities in North America. The red and yellow pigments of Monascus purpureus, such as monascorubin and monascin, have been purified and extensively studied (Fielding et al., 1961, J Chem Soc, 4579-4589). The culture conditions and its effect on pigmentation of Monascus purpureus have also been studied (Broder et al., 1980, J Food Sci, 45:567-469). Antibacterial activity, especially against Bacillus species, was also detected in Monascus purpureus extract (Wong, 1977, Plant Physiol, 60:578-581). The Red Rice of the traditional methods has been shown to be of little value and thus has gradually fallen out of use in medical applications. The traditional Red Rice has little effect of reducing blood lipids, and thus has never been used as a cholesterol lowering agent.
Hyperlipidemia and Dietary/Medical Intervention
Lipids and lipoproteins play an essential role in transporting fat-derived metabolites between organs for absorption, metabolism, and distribution (Felig et al., 1975, N Eng J Med, 293:1078-1084). The susceptibility to dietary-induced elevations in blood lipids including cholesterol is extremely common. The interaction of genetic predisposition and a high fat, high caloric diet coupled with underactivity can lead to heart disease, hypertension, hypertriglyceridemia, and diabetes in a significant proportion of the United States population.
High serum cholesterol is a major risk factor for coronary artery disease. Cholesterol is a major component of atherosclerotic plaque. Other associated lipid abnormalities, including hypertriglyceridemia especially in the presence of lowered HDL cholesterol levels, have been recognized as contributing to the risk of cardiovascular disease. There is a reciprocal relationship between elevated triglyceride levels and lowered HDL levels.
The level of cholesterol in circulation results from the balance between production of apoB-100 particles and its removal from the circulation. Cholesterol is synthesized from acetyl-CoA via a series of more than 20 enzymatic reactions. This biosynthetic pathway is mainly regulated by the activity of HMG-CoA reductase (hydroxymethylglutaryl coenzyme A reductase), which catalyzes the reduction of HMG-CoA to mevalonate. Since the majority of cholesterol circulating is endogenously synthesized in the liver, and not derived from dietary cholesterol, inhibitors of enzymes that are involved in the biosynthesis of cholesterol have been explored as drugs for the treatment of hypercholesterolemia (Grundy, New Eng J Med (1988) 319:24-33).
One class of compounds inhibits cholesterol biosynthesis by competing with a natural substrate (HMG-CoA) for the key enzyme in the cholesterol biosynthetic pathway, HMG-CoA reductase. The first such hypocholesterolemic compound discovered was compactin, which was isolated from cultures of Penicillium citrinum by Akira Endo (Endo et al., J Antibiotics (1975) 29:1346-1348, see also U.S. Pat. Nos. 3,983,140, 4,049,495, and 4,137,322). The hypocholesterolemic activity of this compound was demonstrated in several animal species (Tsujita et al., Atherosclerosis (1979) 32:307-313). Thereafter, a hypocholesterolemic compound structurally related to compactin was independently discovered by Endo in fermentation products of Monascus ruber (the active compound was named monacolin K; Endo, J Antibiotics (1979) 32:852-854; Endo, J Antibiotics (1980) 33:334-336; see also German patents DE 3051175, 3051099 and 3006216; British patents GB 2046737 and 2055100), and by another group from cultures of Aspergillus terreus. The active compound was also named mevinolin, lovastatin or Mevacor.TM.; Tobert et al., J Clin Invest (1982) 69:913-919), and has been available in the United States since 1987 as a prescription drug. The efficacy and long term adverse effect of this active compound has been reviewed (Tobert, Am J Cardiol, 62:28J-34J). The isolated active compound, its derivatives and methods of production from Aspergillus have been reported; see U.S. Pat. Nos. 4,231,938, 4,342,767, 4,294,926, 4,319,039, 4,294,926, 4,294,846, and 4,420,491.
Although monacolin K or mevinolin has been successfully used to treat hypercholesterolemia, the compound has little or insignificant effect on the serum level of triglycerides. Other lipid regulating agents that have been used to treat hypertriglyceridemia, especially type IV and V hyperlipidemia, include nicotinic acid (e.g., niacin), and fibric acid derivatives (e.g., gemfibrozil and clofibrate). However, the uses of such agents are restricted because of their side effects, for example, high doses of niacin may cause gastric irritability, hyperuricemia, hyperglycemia, pruritus, and gemfibrozil may lead to malignancy, gall-bladder diseases, and abdominal pain. Moreover, the risk of myositis and rhabdomyolysis that can result in renal failure increases when monacolin K is combined with gemfibrozil, clofibrate or niacin. Such combinations are only used with careful supervision in special situations that warrant the risk (The Merck Manual, 1992, 16th edition, pages 1044-1046). High concentrations of serum triglycerides are known to be a risk factor for a variety of disease states and can lead to medical complications. Thus, there is a need for the development of a composition that accomplishes the reduction of the serum levels of both cholesterol as well as triglycerides. Regular exercise, proper nutrition, and weight reduction programs can prevent or reduce the incidence of common chronic diseases such as heart disease associated with elevations of blood lipids (Pi-Sunyer, Am J Clin Nutr (1991) 53:1595S-1603S). The role of diet in maintaining optimal health, and in slowing and reversing the progression of disease, has been the subject of much research and public attention. The development of an effective dietary supplement for use in the treatment of mixed hyperlipidemia, which could be used either with or without dietary changes, would be a significant benefit.